Therapeutics based on nucleic acids (NA) promise to revolutionize treatment of multiple diseases but their widespread use is currently limited by the lack of efficient delivery methods. We have recently developed a new NA delivery platform based on polymeric CXCR4 inhibitors (PCX) suitable as dual-function systems for simultaneous NA delivery and inhibition of CXCR4 chemokine receptor. The objective of this 1-year Phase I project is to use the PCX platform to develop an innovative combination treatment of cholangiocarcinoma using PCX/microRNA nanoparticles. Clinical and experimental studies show that CXCR4 expression is associated with more aggressive disease, higher primary tumor burden, more metastases, and shorter overall survival in cholangiocarcinoma. The hypothesis of this project is that using PCX to deliver miR106b inhibitor, identified in our preliminary studies s potential target in cholangiocarcinoma, will lead to improved overall anticancer activity. We will accomplish the objectives through pursuing the following specific aims: 1) optimize PCX/microRNA formulation parameters to obtain nanoparticles capable of simultaneous CXCR4 inhibition and microRNA delivery in cholangiocarcinoma and 2) determine if delivery of miR106b inhibitor by PCX improves overall survival in orthotopic rat model of cholangiocarcinoma. The approach is innovative because of the dual-function design of nanoparticles with CXCR4 inhibitory activity and microRNA delivery. The proposed research is significant because it will establish widely applicable and versatile NA delivery platform that target chemokine networks as a way of improving therapeutic outcomes in cancer and other diseases with involvement of CXCR4.